Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a method for the preparation of compositions, preferably pharmaceutical compositions, in form of expanded, mechanically stable, lamellar, porous, spongue-like or foam structures out of solutions and dispersions.
• This method comprises the steps of a) preparing a solution or a homogeneous dispersion of a liquid and a compound selected from the group consisting of one or more pharmaceutically active compounds, one or more pharmaceutically suitable excipients, and mixtures thereof, followed by b) the expansion of the solution or the homogeneous dispersion without boiling.
• the invention also relates to the compositions, their further processing and any corresponding dosage forms obtainable by the above method.
• the way of downstreaming the pure drug substance into the final market formulation normally comprises several fundamental operations such as milling, seizing, wet or dry granulation, slugging, encapsulation etc.
• Today, many of these processes are designed for manufacturing large amounts of material, e.g. high-speed tabletting. Thereby mechanical energy, produced by impact, pressure or shear stress, is being conducted to the material. Very often this leads to melting, decomposition or inactivation of the drug substance. Thus caused deposits or incrustations may induce interruption of the process or even destruction of the machines.
• the drug substance has normally to be mixed, blended or granulated with different pharmaceutical excipients, such as lubricants, filler, binder, flowing or dispersing agents etc.
• pharmaceutical excipients such as lubricants, filler, binder, flowing or dispersing agents etc.
• the final composition as well as the corresponding dosage form is also supposed to have very specific properties before, during or after application.
• bulk materials powders, granules, pellets, tablets etc.
• dry suspensions must show extremely dispersibility in liquids; tablets have to disintegrate either very fast or very slowly after being swallowed.
• a sufficient wettability of drug particles in gastric or intestinal fluids is a prerequisite for good solubility and absorption.
• pharmaceutical powders or granules need sufficient bulk density for tabletting or encapsulation. Depending on dose these important galenical properties can be affected very badly by having a drug substance or excipient with unsuitable physico-chemical properties (e.g. low melting point; low solubility etc.).
• the problem underlying the present invention is therefore to provide a new process and new compositions minimizing the above mentioned disadvantages.
• a method for the preparation of a pharmaceutical composition comprising the steps of a) preparing a solution or a homogeneous dispersion of a liquid and a compound selected from the group consisting of one or more pharmaceutically active compounds, one or more pharmaceutically suitable excipients, and mixtures thereof, followed by b) expansion of the solution or homogeneous dispersion without boiling.
• compositions can be readily expanded and solidified within their capsule shell, blister pack etc. because of their low filling volume.
• Examples for resulting benefits and possibilities with respect to physico-chemical and biopharmaceutical properties are protection and stabilization of pharmaceutically active compounds or pharmaceutically suitable excipients during processing and storage; expansion of shelf life; elimination of incompatibilities, independent from original properties desired physico-chemical characteristics can be generated according to the material used for embedding; the resulting morphology or the method of downstreaming (i.e. improved wettability, flowability, solubility etc.); taste-masking; reduction of side effects; higher bioavailability (especially for a pharmaceutically active compound solidified as amorphous glass) and/or control of release characteristics.
• solution means a physical system consisting of at least two
• dispersion means a physical system consisting of at least two phases. One of the phases is the dispersion medium, wherein one or more compounds (second or third phase) are uniformly distributed.
• boiling refers to the vaporisation of a liquid in case the pressure exerted by the surroundings upon a liquid is equalled by the pressure exerted by the vapour of the liquid; under this condition, addition of heat or reduction of pressure exerted by the 25 surroundings results in the transformation of the liquid into its vapour without raising the temperature.
• glass-matrix forming material refers to pharmaceutically active compounds or pharmaceutically suitable excipients which appear in the amorphous state after solidification.
• epibedding material refers to substances which are able to coat, enclose, separate, protect or inertize other materials.
• expansion means that the solution or homogeneous dispersion develops an increased volume and surface induced by a change in pressure and is thereby characterized by a coherent, lamellar, foam-, spongue- or cake-like structure.
• polyol in connection with the present invention refers to a material out of the group of carbohydrates such as maltodextrin.
• gum refers to a material which consists of a mixture of polysaccharides such as xanthan.
• polymer refers to a material which is a macromolecule (natural or synthetic substance). It can be a homopolymer (i.e. polyethylenglycol) or a copolymer (i.e. polymethacrylate).
• lipase inhibitor refers to compounds which are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases.
• lipases for example gastric and pancreatic lipases.
• orlistat and lipstatin as described in U.S. Patent No. 4,598,089 are potent inhibitor of lipases.
• Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin.
• Other lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al, /. Antibiot., 47(12):1369-1375 (1994)).
• lipase inhibitor refers also to synthetic lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases.
• lipase inhibitor also comprises pharmaceutically acceptable salts of these compounds.
• lipase inhibitor also refers to 2-oxy-4H- 3,l-benzoxazin-4-ones which have been described in International Patent Application WO00/40569 (Alizyme Therapeutics Ltd.), e.g.
• lipase inhibitor refers to orlistat.
• the resulting pharmaceutical composition is a solid or gel-like composition, preferably a solid composition.
• the method is followed by drying and/or cooling the composition.
• This method is especially useful for the preparation of pharmaceutical compositions.
• the solution or homogeneous dispersion is expanded by decreasing pressure.
• the solution or homogeneous dispersion is prepared by a liquid and a pharmaceutically active compound or pharmaceutically suitable excipient.
• the solution or dispersion is prepared by adding both a pharmaceutically active substance and a pharmaceutically suitable excipient to the liquid.
• the liquid used in the above method should be easy to evaporate or vaporizable and maybe selected from the group consisting of water (i.e. purified, deionised, distilled or sterilised water), aqueous buffer solutions or isotonics (i.e. hydrogen carbonate buffer pH 7.38), a nutrient medium or culture broth (i.e. peptone bouillon), alcohols (i.e. ethanol or isopropyl alcohol), ketones (i.e. acetone), ethers (i.e. diethyl ether), liquid hydrocarbons (i.e. octane), oils (i.e. essential oils such as camomile oil) and synthetics (i.e. plasma expander such as dextranes) but may not be limited to these. Also mixtures of the liquids mentioned above maybe useful for the method of the present invention.
• the liquid is an aqueous buffer and/or an isotonic solution.
• the homogeneous dispersion may have the form of a colloid, sol, gel, liquid crystal, emulsion, paste, suspension or an ointment.
• solutions or homogeneous dispersions may be prepared by pouring the liquid or mixture of liquids into a planetary (or comparable) mixer, followed by dissolving and/or dispersing the pharmaceutically active compound(s) or pharmaceutically suitable excipient(s) in the liquid or mixture of liquids until said homogeneous dispersion is prepared. While mixing with the liquid or mixture of liquids the material(s) can be in the dry state, dissolved, dispersed or melted. Thereby or afterwards further compounds, excipients or liquids may be added.
• solutions or homogeneous dispersions may be prepared by putting the pharmaceutically active compound(s), pharmaceutically suitable excipient(s) or a mixture thereof into a planetary (or comparable) mixer, followed by wetting, dissolving and/or dispersing the material(s) with the solvent or mixture of solvents until said solution or homogeneous dispersion is prepared. Thereby or afterwards further compounds, excipients or liquids maybe added.
• the mixing or dispersing process may be supported by the use of i.e. a static mixer, microfluidizer, homogeniser, kneading devices, high shear forces, ultrasound, an ointment mill or other devices known by the art.
• the viscosity of said homogeneous solution or dispersion can be either low or high, provided that the mass remains feedable or spreadable.
• the solution or dispersion is transformed into an expanded structure by exposing it to a change in pressure, as by vacuum or by puffing and is dried thereby or by contact, convection, radiation, sonification, high frequency, dry (hot or cold) gas or with the help of some desiccants like organic solvents, silica gel etc.
• said homogenized solution or dispersion is normally pumped, distributed, spread or put either on a plate, sieve, belt, roll etc. or in a capsule shell, blister pack, vial, jar, syringe or other suitable form. Then, almost immediately (continuous process) or after a short time (batch process) a controlled change in pressure leads to said expanded structure.
• expansion may be carried out by adjusting pressure conditions in a way that said homogenized solution or dispersion shall not boil.
• pressure conditions may be varied, temperature may be changed or each drying method known by the art may be applied to get the desired residual solvent level. Drying can be an internal or external process and may be supported by vibration, fluidization or any other kind of well known technique that helps removing the fluid, solvent or the saturated gas phase.
• the above described variation of temperature and/or pressure conditions maybe carried out in several steps (batch process) or in different zones (continuous process) wherein a final cooling step may be included.
• the dried and optionally cooled structure expires a long shelf life and can easily be cut, crushed, milled respectively pulverized into a free flowing powder that on the one hand provides easy downstream processing like e.g. wet or dry agglomeration, (melt-)granulation, slugging, tabletting, compaction, pelletization, encapsulation or any other kind of filling process and on the other hand has excellent reconstitution properties in cold or tempered liquids or body fluids whereby the properties and efficacy of any embedded pharmaceutically active compounds or pharmaceutically suitable excipients are maintained.
• wet or dry agglomeration, (melt-)granulation, slugging, tabletting, compaction, pelletization, encapsulation or any other kind of filling process and on the other hand has excellent reconstitution properties in cold or tempered liquids or body fluids whereby the properties and efficacy of any embedded pharmaceutically active compounds or pharmaceutically suitable excipients are maintained.
• the described new method for preparing pharmaceutical compositions furthermore provides the possibility to create the expanded, sufficient dense structure directly in its final formulation or packaging ready for use.
• the initial process for creating and drying said expanded structure can be batchwise (e.g. in a vacuum drying oven) or continuously (e.g. on a vacuum drying belt) or with the help of other techniques known by the art.
• the compound of step a) is a pharmaceutically active compound. In another preferred embodiment, the compound of step a) is a pharmaceutically suitable excipient.
• the present invention refers to a method of preparing a pharmaceutical composition
• a method of preparing a pharmaceutical composition comprising the steps of a) preparing a homogeneous solution or dispersion by mixing a pharmaceutically active compound and/or a pharmaceutically suitable excipient with a liquid or a mixture of liquids in a sufficient amount to create a homogeneous dispersion, b) exposing the dispersion to a change in pressure without boiling, and c) optionally drying and/ or cooling the composition.
• the above methods may also comprise the steps of a) preparing a solution or homogeneous dispersion by mixing a pharmaceutically active compound and a liquid or a mixture of liquids in a sufficient amount to create a solution or homogeneous dispersion, b) exposing the solution or dispersion to a change in pressure without boiling, and c) optionally drying and/or cooling the composition.
• the above described process is especially useful for the preparation of pharmaceutical compositions. Suitable pharmaceutically active compounds for this process may not be limited to any special group.
• the above described method for preparing pharmaceutical compositions is basically supposed to be a powerful tool whenever physico-chemical, technical, galenical or biopharmaceutical problems occur during or after development of pharmaceutically relevant products (i.e. drugs, medicaments, vitamins, medical devices). Nevertheless lipase inhibitors are especially preferred compounds to be used in the above process, preferably orlistat.
• Orlistat a gastrointestinal lipase inhibitor, also known as orlistat, is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Patent No. 4,598,089, issued July 1, 1986, which also discloses processes for making orlistat and U.S. Patent No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123. Other examples for pharmaceutically active compounds are neuraminidase inhibitors, e.g. oseltamivir and insulin sensitizers, e.g.
• the above solutions or dispersions further comprise an embedding or glass matrix-forming material.
• the embedding or glass matrix-forming material is a polyol, gum, polymer, or pharmaceutically acceptable salts thereof.
• the embedding or glass matrix-forming material may be the pharmaceutically active compound, higly dispersed as crystalline respectively solidified in the amorphous state or the pharmaceutically suitable excipient, preferably a polyol, e.g. a carbohydrate.
• the embedding or glass matrix-forming material maybe amorphous, partly or fully crystalline.
• the carbohydrate as pharmaceutically suitable excipient may be selected from the group consisting of e.g. maltodextrin, trehalose, cellobiose, glucose, fructose, maltulose, iso-maltulose, lactulose, maltose, gentobiose, lactose, isomaltose, maltitol, lactitol, erythritol, palatinitol, xylitol, mannitol, sorbitol, dulcitol and ribitol, sucrose, raffinose, gentianose, planteose, verbascose, stachyose, melezitose, dextran and further inositol but may not be limited to these.
• the carbohydrate is maltodextrin.
• the carbohydrate is trehalose.
• the carbohydrate is maltitol.
• the term "maltodextrin” preferably refers e.g. to Glucidex Roquette
• the term “trehalose” preferably refers e.g. to Trehalose Merck
• the term maltitol preferably refers e.g. to Maltisorb Roquette.
• compositions for use may be selected from the group of polymers, gums and their salts such as polyethylenglycol; modified or substituted starch (e.g. pregelatinized starch, hydroxyethylstarch, sodium starchoctenylsuccinate, inulin etc.); modified or substituted cellulose (e.g.
• pectin carrageenan gum
• glucomannan polymethacrylates
• propylene glycol alginate shellac
• sodium alginate tragacanth xanthan gum
• chitosan but may not be limited to these.
• Some of the mentioned materials maybe fully amorphous or can also appear partially or fully in the crystalline state.
• any pharmaceutically suitable excipient for this kind of process can generally be selected from all possible groups of adjuvants that help transform the pharmaceutically active compound into its final formulation, modify or optimize its efficacy, change its properties, immobilize its molecules or preserve its stability.
• the invention is appropriate to improve desirable properties of an inert pharmaceutically suitable excipient as well as to mask properties undesirable.
• Some of the preferred groups of pharmaceutically suitable excipients comprise compounds selected from solvents, solubiliser, dissolution enhancer, salt forming agents, (volatile) salts, buffers, effervescent agents, stabilizing agents, gel former, tensides, lipids, fatty acids, antioxidants, synergists, chelating agents, preservatives, filler, bulking agents, carrier, adsorbents, binder, disintegrants, glidants, lubricants, separating agents, flow promoter, coating agents, retarding agents, coloring agents, pigments, odor and taste adjusting/-masking agents, resorption enhancer, moisture adjusting agents, flocculating agents etc.
• the invention refers to the above methods, wherein the pharmaceutically active compound is selected from the group consisting of e.g. molecules, drugs, vitamins, minerals, trace elements, enzymes, cells, sera, vaccines, proteins, viruses, bacteria, nucleic acids, complexes, liposomes or nanoparticles but may not be limited to these.
• the pharmaceutically active compound is selected from the group consisting of e.g. molecules, drugs, vitamins, minerals, trace elements, enzymes, cells, sera, vaccines, proteins, viruses, bacteria, nucleic acids, complexes, liposomes or nanoparticles but may not be limited to these.
• the present invention refers to methods, wherein the solution or dispersion comprises a tenside.
• Tensides in the sense of the present invention refer to pharmaceutically suitable excipients with emulsifying, stabilizing, solubilizing, wetting, anti-foaming or spreading properties. These adjuvants have an amphiphilic character and influence the interfacial tension between different phases.
• the term "tensides” comprises anionic tensides or co-emulsifier (i.e. detergents, sulfonates, sodium lauryl sulfate, docusate sodium, casemate sodium, salts of fatty acids), cationic tensides (i.e.
• non-ionic tensides i.e. polyoxyethylen fatty acid esters, e.g. polyoxyl 40 stearate, sucrose fatty acid esters, cetyl alcohol, fatty acid esters, cetostearyl alcohol, cholesterol, sorbitan fatty acid esters, polysorbats, poloxamer, tocopheryl polyethylene glycol succinate
• amphoteric tensides i.e. phospholipids, ampholyts, proteins.
• the tenside is a polyoxyethylene fatty acid ester.
• the tenside is a phospholipid.
• the tenside selected from the group consisting of sodium lauryl sulfate, docusate sodium, caseinate sodium, salts of fatty acids, quaternary amines, cethylpyridiniumchloride, polyoxyethylene fatty acid esters, sucrose fatty acid esters, cetyl alcohol, fatty acid esters, cetostearyl alcohol, cholesterol, sorbitan fatty acid esters, polysorbats, poloxamers, tocopheryl polyethylene glycol succinate, and phospholipids.
• the above described method refers to solutions and dispersions comprising from 3 to 99.99 % w/w solvent(s) and 0.01 to 97 % w/w pharmaceutically active compound(s) or 0.01 to 97 % w/w pharmaceutically suitable excipient(s).
• the invention also refers to a method as described above, wherein the solution or dispersion comprises from 3 to 99.98 % w/w solvent(s), 0.01 to 96.99 % w/w pharmaceutically active compound(s), and 0.01 to 96.99 % w/w pharmaceutically suitable excipient(s).
• the above described solutions or dispersions may comprise from 3 to 99.98 % w/w solvent, 0.01 to 96.99 % w/w pharmaceutically active compound, and 0.01 to 96.99 % w/w of a polyol. More preferably, the above described solutions or dispersions maybe prepared from 3 to 99.97 % w/w solvent, 0.01 to 96.98 % w/w pharmaceutically active compound, 0.01 to 96.98 % w/w polyol and 0.01 to 96.98 % w/w of a tenside.
• the invention refers to the above methods, wherein the dispersion comprises the solution or dispersion comprises from 3 to 99.98 % w/w solvent, 0.01 to 96.99 % w/w pharmaceutically suitable excipient and 0.01 to 96.99 % w/w of a polyol, and to methods, wherein the solution or dispersion comprises from 3 to 99.98 % w/w water or mixtures of water/ ethanol, 0.01 to 96.99 % w/w phospholipid and 0.01 to 96.99 % w/w maltodextrin.
• the invention also refers to the above methods, wherein the solution or dispersion comprises from 3 to 99.98 % w/w solvent, 0.01 to 96.99 % w/w pharmaceutically active compound and 0.01 to 96.99 % w/w of a pharmaceutically suitable excipient.
• the invention relates to the above methods, wherein the solution or dispersion comprises from 5 to 95 % w/w water or a mixture of water/ ethanol, 1 to 91 % orlistat, 3.9 to 93.9 % maltodextrin and 0.1 to 90.1 % w/w of one or more pharmaceutically acceptable excipients as decried above.
• An especially preferred embodiment of the present invention refers to a method wherein the solution or dispersion is made from of 5 to 95 % w/w solvent, preferably water or mixtures of water/ethanol, 1 to 91 % w/w orlistat, 3.9 to 93.9 % w/w maltodextrin and 0.1 to 90.1 % w/w of polyoxyethylene fatty acid ester.
• a further preferred embodiment of the present invention refers to the above methods wherein the solution or dispersion comprises from 5 to 95 % w/w water or mixtures of water/ethanol, 1 to 91 % w/w orlistat, 1 to 91 % w/w lipids, preferably trimyristin, 2.9 to 92.9 % w/w maltodextrin and 0.1 to 90.1 % w/w polyoxyethylene fatty acid ester.
• the invention relates to the above methods, wherein the solution or dispersion comprises from 3 to 99.98 % w/w isopropylalcohol, 0.01 to 96.99 % w/w oseltamivir, and 0.01 to 96.99 % w/w polymethacrylate.
• the above method refers to the preparation of compositions
• the solution or dispersion is prepared by pouring the solvent or mixture of solvents into a mixer, e.g. a planetary mixer or another suitable mixing devices known by the art, optionally adding a tenside or other suitable excipients and distributing them in the solvent or mixture of solvents.
• a mixer e.g. a planetary mixer or another suitable mixing devices known by the art
• the final solution or dispersion develops by optionally adding the polyol or other suitable excipients stepwise and by stirring, mixing, scraping or kneading continuously.
• Dependent on viscosity particle desagglomeration may be optimized by using e.g.
• Intrinsic particle size may be controlled by laser diffraction or with a "grindometer” (metal block with a graduated groove and a scraper). The sequence of processing steps is variable and can be changed, if appropriate.
• the viscosity of the solutions or dispersions may be increased or decreased by adding one or more pharmaceutically suitable excipients.
• the expansion may be carried out within a temperature range of 20 to 35 °C and a reduction of pressure from 30 to 150 Torr, more preferably from 30 to 45 Torr. This may be performed by spreading the solution or homogeneous dispersion on plates or more preferably on sieves, screens or nets and putting them into a vacuum drying oven (or another suitable device known by the art) which is tempered in the range from 20 to 35 °C. With regard to the chosen temperature, reduction of pressure in the range from 30 to 150 or more preferably from 30 to 45 Torr creates the desired dense, expanded structure without boiling.
• temperature and pressure conditions may be varied, presupposed that the evaporated liquid does not boil during the expansion step.
• an optional drying and/or cooling step may be carried out by varying temperature and/or pressure conditions.
• a drying process may be an internal or external process and the drying temperature may be higher or lower than the expansion temperature.
• the drying pressure may be higher or lower than the expansion pressure.
• the drying may be supported by vacuum, heating, sublimation, vibration, fluidization, radiation, contact, convection, sonification, high frequency, dry (hot or cold) gas or with the help of some desiccants (i.e. organic solvents, silica gel etc.) or any other kind of well known technique that helps removing the fluid, solvent or the saturated gas phase.
• an additional cooling step maybe applied after expansion and optional drying of the structure.
• the cooling temperature may be higher or lower than 0 °C and lower than the drying temperature.
• the cooling process may be an internal or external process.
• the expansion, optional drying and/or cooling of the structure is carried out in several steps (batch process) or in different zones (continuous process).
• a continuous process maybe carried out with a vacuum drying belt, a vacuum drying roll or other suitable devices known by the art.
• the present invention refers also to the compositions obtainable by the above methods.
• compositions obtainable according to the present invention may be characterized by assay, volume, density (preferably bulk density of the crushed material), particle size distribution, surface measurement, relative humidity, residual solvent level, solid matter content, wettability, solubility, stability, disintegration time, release characteristics, X-ray diffraction, dynamic vapor sorption, microcalorimetry, thermogravimetry, differential scanning calorimetry etc.
• the expanded, readily dried and crushed compositions obtainable by the present invention are characterized by a residual solvent level between 0.1 and 99.9 %, more preferably between 1 and 10 % and most preferably between 2 and 5 % w/w.
• the bulk (poured) density is between 0.1 and 0.9, more preferably between 0.2 and 0.8 and most preferably between 0.3 and 0.6 g/cm 3 .
• the particle size distribution of these compositions maybe between 50 and 600, more preferably between 200 and 400 ⁇ m.
• the present invention refers to a pharmaceutical composition, comprising 0.2 to 10 % w/w residual water or mixtures of water/ethanol, 1 to 96 % w/w orlistat, 3.7 to 98.7 % w/w maltodextrin or maltitol and 0.1 to 95.1 % w/w of one or more pharmaceutically acceptable excipients as described above, e.g. a polyoxyethylene fatty acid ester.
• the present invention relates to a pharmaceutical composition comprising from 0.2 to 10 % w/w residual isopropyl alcohol, 1 to 98.8 % w/w oseltamivir, and 1 to
• compositions are characterized by a residual solvent level between 0.1 and
• the bulk (poured) density is between 0.1 and 0.9, more preferably between 0.2 and 0.8 and most preferably between 0.3 and 0.6 g/cm 3 .
• the particle size - re distribution of these compositions may be expressed as "d' (63.2 %) value" between 50 and 600, more preferably between 200 and 400 ⁇ m.
• compositions obtainable according to the above methods may be blown, cut crushed, sieved, milled, chopped, comminuted or shredded into a (free flowing) powder.
• the powder may be mixed, combined, blended, granulated, tableted or processed with one or more pharmaceutically active compounds or pharmaceutically suitable excipients.
• the compositions may be processed into a dust, aerosol, powder, granule, pellet, tablet, dragee, capsule, dry solution, dry syrup, dry emulsion, dry suspension or others known by the art.
• compositions obtainable according to the invention maybe directly prepared in their final formulation and dosage form, respectively and more preferably directly in its packaging.
• the dosage form maybe selected form the group consisting of a xerogel, tablet or capsule but may not be limited to these.
• the dosage form may also be directly prepared in its packaging.
• the packaging maybe selected from the group consisting of a blister pack, vial, jar, sachet or syringe but may not be limited to these.
• the final product corresponding to the methods of the present invention may be a drug, medicament, vitamin, instant drink or medical device but may not be limited to these.
• Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 120 to 360 mg, most preferably 120 to 180 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day.
• the subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
• the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat.
• treatment be administered to a human who has a strong family history of functional dyspepsia and has obtained a body mass index of 25 or greater.
• the invention refers to the use of the below defined compositions for the preparation of drugs, medicaments, vitamins, medical devices etc. useful for treatment and prevention of diseases as mentioned above.
• compositions according to the invention including orlistat as pharmaceutically active compound.
• the amount of solvent necessary for preparing the homogeneous dispersion is expressed as percentage of dry mass (w/w).
• the original solvent content of the raw materials was not taken into consideration.
• This composition was used to improve flowability, wettability, dispersibility, efficacy and stability of the pharmaceutically active compound.
• an easy downstream processing into a powder respectively into capsules or tablets is enabled:
• This example describes a composition according to the invention including oseltamivir as pharmaceutically active compound.
• the amount of solvent necessary for preparing the homogeneous dispersion is expressed as percentage of dry mass (w/w).
• the original solvent content of the raw materials was not taken into consideration.
• This composition was used to perform a taste-masking, to improve stability and shelflife, to reduce side effects and to prevent incompatibilities:
• compositions according to the invention including phospholipid as pharmaceutically suitable excipient.
• the amount of solvent necessary for preparing the homogeneous dispersion is expressed as percentage of dry mass (w/w).
• the original solvent content of the raw materials was not taken into consideration.
• This composition was used to prevent stability problems and incompatibilities: Lecithin 30.0 % w/w
• This example describes a placebo composition respectively the direct preparation of its final dosage form according to the invention including maltodextrin and hydroxypropylmethyl cellulose as pharmaceutically suitable excipients.
• the amount of solvent necessary for preparing the homogeneous dispersion is expressed as percentage of dry mass (w/w). The original solvent content of the raw materials was not taken into consideration.
• This composition was used to demonstrate manufacturability, stability and weight uniformity of the directly prepared dosage forms in a blister pack:
• Hydroxypropylmethyl cellulose 20.0 % w/w
• the chamber temperature was then increased to 50 °C for about 120 minutes.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
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• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Dispersion Chemistry (AREA)
• Virology (AREA)
• Molecular Biology (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Inorganic Chemistry (AREA)
• Diabetes (AREA)
• Biochemistry (AREA)
• Child & Adolescent Psychology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Pulmonology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2001
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• 2007
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